6-fluoro-11-oxygenated progesterones and process for preparing same



United States Patent 2,838,501 Patented June 10, 1953 fiice G-FLUORO-ll-OXYGENATED PROGESTERONES AND PROCESS FOR PREPARING SAME 1 Allan Campbell, Kalamazoo Township, Kalamazoo County, John C. Babcock, Portage'Township, Kalamazoo County, and John A. Hogg, Kalamazoo Township,

Kalamazoo County, Mich., assignors to The Upjohn iCompany, Kalamazoo, Mich., a corporation of Michgan Application November 29, 1957 Serial No. 699,503

25 Claims. (Cl. 260239.55)

The present invention relates to steroid compounds and is more particularly concerned with 6'-fluoro-11fl-hydroxy- No Drawing.

'p'rogesterone, G-fluoro-lla-hydroxyprogesterone and 6- fluoro-l l-ketoprogesterone and intermediates therefor, and a process for the production thereof.

The new compounds and the process of the present invention are illustratively represented by the following wherein R is analkylene radical containing one to eight carbon atoms, inclusive, the attaching oxygen-to-carbon bondsare separated by a chain of at leasttwo and not more than three carbon atoms, and R is keto, ct-hydroxy or p-hydroxy.

The process of the present invention comprises treating an ll-oxygenated progesterone 3,20-bis-(alkylene ketal) (I), in which the ll oxygen function is keto or hydroxy, the alkylene radical contains not more than eight carbon atoms, and the attaching oXygen-to-carb0n bonds are separated by a chain of at least two and not more than three carbon atoms, with a peracid, such as per-. formic, peracetic and pcrbenzoic, to obtain the corresponding ll-oxygenated 5e,6a-oxidopregnane-3,20-dione 3,20-bis-(alkylene ketal) (II); treatingthe thus obtained 5a,6a-0Xid0 compound with a fiuorinating agent such as hydrogen fluoride to obtain the corresponding 1loxygenated 5ot-hydroxy-6B-fluor0pregnane-3,ZO-dione 3, 20-bis-(alkylene ketal) (III); treating the latter bisketal with an aqueous acid in a suitable solvent to remove the ketal groups and produce an ll-oxygenated Sa-hydroXy- 6B-fiuoropr'egnane-3,20-dione (IV), and treating the latter compound with a dehydrating agent such as a base or, preferably, an acid to obtain ll-oxygenated 6-fiuoroprogesterone (V) (both the Ga and 6fl-epimers). To obtain the 6,8-epirner, treatment with a base is preferred, as will be described subsequently.

In the dehydration step, higher concentrations of acid produce the 6a-epimer, while lower concentrations of acid produce the 6;8-epirner. If a base is used, such as aqueous sodium or potassium hydroxide, low concentration and temperature gives the 6fl-epimer While high concentration gives the 6a-epimer. fifl-fluoro-ll-ketoprogesterone and 6,8-fiuoro-1l-fi-hydroxyprogesterone can also be converted to the corresponding oa-fluoro epimers by enolizing agents such as strong mineral acids, e. g., sulfuric, perchloric, hydrochloric, nitric (dilute) and the like. Treatment of the 6fi-epimers with bases such as sodium and potassium hydroxide is also productive of the 6a-epimers.

The above process can be modified without altering the concept of the invention. Depending upon cost and availability of starting materials, yields, and other economic factors, such modification may be desirable. For example, starting with ll-ketoprogesterone, preparing the bis-(alkylene ketal), and following the above process to obtain 5a.hydroxy-6B-fluoropregnane-3,11,20-trione 3, ZO-bis-(alkylene ketal), treating the said compound with lithium aluminum hydride to obtain 5a,11}3-dihydroxy- 6B-fluoropregnane-3,ZO-dione, 3,20-bis-(alkylene ketal), and subjecting the latter compound to hydrolysis and dehydration as described hereinabove is productive of 6- fluoro-llfl-hydroxyprogesterone. Treating 6-fiuoro-11;3 hydroxyprogesterone with chromium trioxide in acetic acid is productive of 6-fluoro-1l-ketoprogesterone.

Starting with lla-hydroxyprogesterone 3,20-bis-(alkylene ketal) (prepared in the manner of Example 1 by substitution of lla-hydroxyprogesterone for ll-ketoprogesterone), treating the lla-hydroxyprogesterone 3, ZO-bis-(alkylene ketal) with peracetic acid to produce 511, 6a-oXido-11a-hydroXypregnane-3,20-dione 3,20-bis-(alkylene ketal), treating the latter compound with hydrogen fluoride to produce 5a,11a-dihydroxy-6,8-fluoropregnane 3,20-dione 3,20-bis-(alkylene ketal), treating the latter compound with aqueous acid in a suitable solvent to produce 511,11a.-dihydroxy-6[3-fiuoropregnane-3,ZO-dione, and dehydrating the thus obtained 5a.,11a-dihydIOXy-6fl fiuoropregnane-3,20-dione with a base or, preferably, with an acid reagent is productive of 6-fluoro-11a-hy dr0Xy-4-pregnane-3,20-dione (6-fltl01O-11a-11YC1IOXYPIO- gesterone). Oxidation of 6-tluoro-1la-hydroxy-progesterone with chromium trioxide in acetic acid is productive of 6-fluoro-1l-ketoprogesterone.

Alternatively, 6-fluoro-1lfi-hydroxyprogesterone and 6-fluoro-1l-ketoprogesterone are produced by treating 1lfi-hydroxypregnenolone or 1lfi-hydroxypregnenolone 3-acetate with peracetic acid to obtain 319,115-dihydroxy- 506,6Ct-0XldOPI'BgIlflI1-20-Ol1 or the 3-acetate; treating the thus produced 3 8,1lfl-dihydroxy-S GwoXidopregnan-ZO- one, or 3-acctate, with hydrogen fluoride to obtain 35,5, 1l,B-trihydroxy-6fi-fluoropregnan-20-one or acetate; if the acetate is made, treating the said acetate with aqueous alkali or acid to hydrolyze the 3fl-acetoxy group to a 3B-hydr0xyl; oridizing the 3B,5a,1lfi-trihydroxy-6;8- fluoropregnan-ZO-one, as by an Oppenauer oxidation using aluminum isopropoxide and acetone, to produce 504,115 dihydroxy 6B fluoropregnane 3,20 dione, and treating the latter compound with a dehydrating agent such as a mineral acid to obtain -fluoro-llfi-hydroxyprogesterone, which can then be oxidized to 6-fluoroll-ketoprogesterone, for example, with sodium di chromate in acetic acid.

It is an object of the instant invention to provide 6-fluoro-11-oxygenated progesterones (both the 6m and the G/S-epimers), wherein the ll-oxygen function is keto, llm-hydroxy or fi-hydroxy, and intermediates for the production thereof, such as ll-oxygenated 50,6oL-GXidO- pregnane-3,20-dione 3,20-bis-(alkylene ketal) having from one to eight carbon atoms in the alkylene chain and ll-oxygenated 5whydroxy-6,8-fluoropregnane-3,20- dione and the 3,20-bis-(alkylene ketals) thereof. It is another object of the instant invention to provide a process for the production of 6-fluoro-ll-oxygenated progesterones and intermediates such as ll-oxygenated 50,6uoXidopregnane-3,ZO-dione, 3,20-bis-(alkylene ketal) and ll-oxygenated 5e-hydroxy-6fl-fluoropregnane-3,ZO-dione and the 3,20-bis-(alkylene ketals) thereof. An additional object of the instant invention is to provide Gct-flllOtO- llfl-hydroxyprogesterone and 6cz-fiLlOfO-l lketoprogesterone. Other objects will be apparent to those skilled in the art to which this invention pertains.

The compounds of this invention possess valuable glycocorticoid and anti-inflammatory activities. Thus, for example, 6a-fluoro-ll-ketoprogesterone has been found to exhibit about two times the glucocorticoid activity of hydro-cortisone and approximately thesarnc anti-inflammatory activity as hydrocortisone, while having little efliect on the normal rates of sodium excretion and water loss. ofi-fluoro-ll-ketoprogesterone has been found to exhibit glucocorticoid activity and is an active uterotrophic agent. oa-fluoro-lIB-hydroxyprogesterone has been shown to have marked anti-inflammatory activity. These compounds are useful in the treatment of inflammatory conditions of the skin, eyes and ears of humans and of valuable domestic animals, as well as contact dermatitis and other allergic reactions. Compositions containing the compounds of the present invention can be prepared for human or animal use by incorporating them in any one of the several dosage forms suit able for such use. Administration of the novel steroids thus can be in conventional dosage forms, such as pills. tablets, capsules, solutions, syrups or 'elixirs for oral use, or in liquid forms which are adaptable to the natural and synthetic cortical steroid. hormones for injectable products.

The novel compounds can also be administered tonically in the form of ointments, creams, lotions and the like, with or without coacting antibiotics, germicides, or other materials forming advantageous combinations therewith.

These compounds are additionally useful as intermediates in the production of 6-fluoro-9a-halo-llB-hyclroxyprogesterone, 6-fluoro-9ct-halo-1l-ketoprogesterone, l-dehydro 6 fluoro 11B hydroxy-progesterone, l dehydro-6-fluoro-l l-ketoprogesterone, l-dehydro-G-fluoTo-Sw halo-lIdhydroxyprogesterone and l-dehydro-6-fluoro- 9m-halo-11-ketoprogesterone, wherein the 9a-halogen is of atomic weight of seventeen to eighty, inclusive, that is, fluorine, chlorine, and bromine. The 906-11310 derivatives are of particular importance because they possess a combination of high anti-inflammatory and glucocorti- '4 coid properties with low concomitant mineralocorticoid activity.

The starting compounds of the instant invention are lloxygenated progesterone 3,20 bis (alkylene ketal), wherein the ll-oxygen function is keto or hydroxy and wherein the alkylene group contains not more than eight carbon atoms.

In carrying out the process of the present invention, a selected ll-oxygenated progesterone 3,20-bis-(alkylene kctal) is dissolved in an inert organic solvent such as chloroform, methylene chloride, ethylene dichloride, carbon tetrachloride, benzene, toluene, or the like, preferably a chlorinated hydrocarbon, and treated with an organic peracid such as performic, peracetic, perpropionic, pcrbenzoic, monoperphthalic acid or other organic peracids. Ten to 500 percent in excess of the theoretical amount is usually employed. The reaction is generally carried out at low temperatures such as between minus ten and plus ten degrees Centigrade, zero to five degrees being preferred. However, higher or'lower temperatures such as about minus thirty to plus forty degrees centi grade are operable.

At the end of the reaction, the mixture is neutralized, preferably with sodium or potassium carbonate or bicarbonate, washed with water, and the thus produced 11- oxygenated 511,60; oxidopregnane 3,20 dione 3,20- bis-(alkylene ketal) recovered by evaporation of the solvent. Recrystallization from organic solvents such as methanol, ethanol, Skellysolve B hexanes, heptanes, benzene, toluene, methylene chloride, ether or the like, provides pure ll-oxygenated 5a,6a-oxido-3,20-dione 3,20- bis-(alkylene ketal).

The thus obtained ll-oxygenated 5a,6aoxidopregnane- 3,20-dione 3,20-bis-(alkylene ketal), dissolved in a suitable organic solvent, is reacted with -a fluorinating agent such as hydrogen fliioride to open the epoxy bond and to give ll-oxygenated 5u-hydroxy-6-fluoropregnane-3,20- dione 3,20-bis-(alkylene ketal). The hydrogen fluoride used can be gaseous hydrogen fluoride, hydrofluoric acid in aqueous solution, preferably of about 48 percent strength, or a metal fluoride releasing hydrogen fluoride when treated by an acid as, for instance, potassium or sodium bifluoride and an acid such as acetic, propionic or mineral acids such as perchloric, sulfuric acid or the like. The reaction is ordinarily performed at between about minus seventy and plus fifty degrees centigrade. If anhydrous hydrogen fluoride is used, usually low temperatures, that is, temperatures between about minus seventy and plus ten degrees, are preferred. The hydrogen fluoride, as for example, can be allowed to enter from a hydrogen fluoride gas cylinder into a vessel not reactive to hydrogen fluoride. If aqueous hydrogen fluoride is used the reaction can be carried out between about zero degrees and room temperature. Similarly, when the hydrogen fluoride is produced in situ by the reaction of a metallic fluoride such as potassium bifluoride and an acid, reaction temperatures between zero and ninety degrees centigrade are operative. At lower temperatures, solvents such as chloroform, methylene chloride, and particularly tetrahydrofuran are used. In the reaction of the epoxide with potassium bifluoride and an acid, organic acids are preferred such as acetic acid, propionic acid. formic acid or the like. However, other solvents such as neopentyl alcohol, isopropanol and the like with mineral acids such as sulfuric acid, perchloric acid or the like can be used. The reaction period is usually between fifteen minutes and four hours, with reaction times of approximately two to three hours usually being suflicient for anhydrous hydrogen fluoride. When potassium bifluoride is used, reaction times of several hours to five days are employed, depending on the temperature of reaction.

After the reaction is terminated the material is isolated by methods well known in'the art such asneutralizing the excess of hydrogen fluoride present with a base, e. g., sodium bicarbonate, potassium bicarbonate, sodium hydro'xide or the like, and'extracting the product with waterimmiscible solvents such as methylene chloride, chloroform, benzene, ether, hexanes and the like. Evaporation of the organic solvents used gives the cr'ude'ma'terial which is purified generally by recrystallization from organic solvents such as methanol, ethanol, acetone, Skellysolve B hexanes, benzene, methylene chloride or the like, to give pure ll-oxygenated 5a-hydroxy-6fi-fluoropregnane- 3,20-dione 3,20-bis-(alkylene ketal). However, with aqueous hydrogen fluoride, the ketal groups hydrolyze, yielding ll-oxygenated 5a-hydroxy-6fl-fiuoropregnane- 3,20-dioue.

The thus obtained ll-oxygenated Sa-hydroxy-Gfl-fluoropregnane-3,20-dione 3,20-bis-(alkylene ketal) is thereupon hydrolyzed in a water-miscible solvent, preferably in an aqueous alkanol or acetone acidic medium. As solvent alkanols, methanol and ethanol are preferred; however, other suitable water-miscible solvents such as tertiary butyl alcohol, propyl alcohol, isopropyl alcohol, dioxane, acetone, acetic acid or the like can be used. To the solution of the steroid is then added an organic or inorganic acid, preferably a mineral acid such as sulfuric acid or hydrochloric acid. Organic acids such as formic, acetic, propionic, and toluenesulfonic, can also be used. After standing, the solution is neutralized with aqueous sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or other alkali solutions and concentrated to give a crude product consisting of ll-oxygenated 5oa-hydroxy-6p-fiuoropregnane-3,20-dione. The crude product can be purified using known techniques, for example, by recrystallization from organic solvents such as acetone, ethyl acetate, Skellysolve B hexanes, methanol, tertiary butyl alcohol, pyridine, ether, or the like, or mixtures thereof to give pure ll-oxygenated 5ahydroxy-6fi-fluoropregnane-3,20-dione.

The thus obtained ll-oxygenated 5a-hydroxy-6fl-fluoropregnane-3,20-dione is thereupon dehydrated. Dehydra- .tion can be effected in alkali or in acid solution.

drogen bromide, sulfuric acid and the like, with gaseous hydrogen chloride preferred. For dehydration with alkali thev steroid is dissolved in methanol, ethanol, dioxane, or other convenient solvents unreactive to the base employed.

The solution is advantageously purged of oxygen by bubbling nitrogen through the solution and then allowed to react with an oxygen-free alkali metal base solution. Sodium or potassium hydroxide are the preferred bases, although alkali metal alkoxides, barium hydroxide, calcium hydroxide, or the like, can be used.

Depending on the amount of acid or base used, the

6aand 6,8isomers are obtained. The dehydration produces at first the 6fi-isomer which, being less stable in strong acid or bases, rearranges to the 6a-isomer. If, at the start of the dehydration reaction, the medium was strongly acidic, only 11-oxygenated oa-fiuoroprogesterone is obtained. A weakly acidic orbasic medium produces ll-oxygenated ofi-fluoroprogesterone, while a strongly basic medium yields the u-epimer, i. e., ll-oxygenated a-fluoroprogesterone. The 6fl-epimer can subsequently be converted to the 6 x-epimer by treatment with strong acid or base.

The dehydration step can also be accomplished using an N-bromoamidesuch as an N-bromoacylamide, e. g., N-bromosuccinimide or N-bromophthalimide.

The thus obtained ll-oxygenated 6-fluoroprogesterone is isolated from the reaction mixture and purified by conventional procedures, such as by diluting with water, and either recovering by filtration or by extracting the mixture with a water-immiscible solvent, methylene chlo ride, chloroform, hexanes, benzene, ether and the like, and evaporating the solvent. The thus obtained solids are purified by conventional procedures, such as recrystallization from an organic solvent, such as methanol, ethanol, Skellysolve B hexanes, ethyl acetate, pyridine, benzene, or the like to obtain the pure ll-oxygenated 6-fluoroprogesterone.

To obtain 6-fluoro-9whalo-llfl-hydroxyprogesterone and 6-fiuoro-9a-halo-1l-kctoprogesterone, 6-fluoro-1l/3- hydroxy-4-pregnene-3,20-dione is dehydrated to the corresponding 6 fluoro 4,9(11) pregnadiene-3,20-dione by methods known in the art, for example, by a dehydrating agent such as phosphorus oxychloride, thionyl chloride, hydrochloric acid or sulfuric acid and acetic acid or by pyrolysis as shown by U. S. Patents 2,640,838 and 2,640,- 839. The dehydration is conveniently effected by reacting the llfi-hydroxy compound with a carboxylic acid N-haloamide or N-haloimide in an organic base and treating the thus produced intermediate ll-hypohalite with dry sulfur dioxide in an organic base. As reagents for the production of an ll-hypohalite, the acid N-haloamide or acid N-haloimide are used wherein the halogen has an atomic number from 17 to 53, inclusive, preferably chlorine or bromine. Examples of such compounds are N-chloroacetamide, N-bromoacetamide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 3-bromo- 5,5-dimethylhydantoin and l,3-dibromo-5,5-dimethylhydantoin, and the like. Ordinarily, an amount in excess of a molar equivalent, calculated on the starting llfihydroxy steroid, is employed. The organic bases employed as solvents in the production of the ll-hypohalite are tertiary amines wherein the amino nitrogen is a member of an aromatic ring, for example, the pyridines, that is, pyridine, alkyl-pyridines, picoline, lutidine, collidine, conyrine, parvuline, or the like, or lower fatty amides such as formamide, methylformamide and dimethylformamide. The base is preferably employed in a large molar excess, calculated onthe starting llB-hydroxy steroid, for example, ten molar equivalents per mole of steroid, and is preferably the sole reaction solvent. The reaction to produce an ll-hypohalite isgenerally conducted under anhydrous conditions, the mixture containing less than 0.1 molar equivalent of water calculated per mole of steroid. Large proportions of water decrease the yield. The temperature of the reaction is between minus forty and plus seventy degrees centigrade, the lower limit being determined by the solubility of the steroid and reagents and the upper limit being determined by the amount of side reaction which normally accompanies reactions involving any halo compounds at higher temperatures. Ordinarily, room temperature (twenty to thirty degrees centigrade) is preferred for convenience and because of the consistently high yields of the desired product which are obtained at this temperature. A reaction period between five minutes to three hours is usually employed; at higher temperatures-above thirty degrees Centigradeshort reaction times are suflicient to effect completion of the reaction.

The thus produced 6-fluoro-1lB-hydroxy-4-pregnene- 3,20-dione llli-hypohalite is then treated with anhydrous sulfur dioxide in the presence of an organic base as described hereinbefore. The anhydrous sulfur dioxide can be in the form of gaseous or liquid sulfur dioxide or in the form of a material which in situ produces sulfur dioxide, for example, alkali metal hyposulfites. The reaction temperature ranges substantially within minus forty and plus seventy degrees centigrade, preferably room temperature (twenty to thirty degrees centigrade). The thus obtained product, 6-fluoro-4,9(l1)-pregnadiene-3,20- dione, is isolated from the reaction mixture by conventional means such as extraction after the reaction mixture has been poured into an excess of water. Organic waterimmiscible solvents such as ether, chloroform, methylene it): chloride, carbon tetrachloride, ethyl acetate, benzene,

hexanes, or the like, are used for the extraction. The thus obtained extracts are conveniently WZiSllfiidliEd and thereupon evaporated to give the crude 6 -fiuoro-4,9(ll)- pregnadiene-3,20-dione which is purified by conventional means such as recrystallization or chromatography, as deemed necessary.

steroid, 6-fluoro-4,9(l1)-pregnadiene-3,20-dione, is dissolved in an organic solvent such as methylene chloride, tertiary butyl alcohol, dioxane, tertiary amyl alcohol, or the like, and reacted at room temperature with the hypobromous or hypochlorous acid releasing agent in the presence of an acid. Such hypohalous acid releasing agents include N-bromoacetamide, N-chloroacetamide, N- bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide, or the like, in the presence of water and an acid such as perchloric acid, dilute sulfuric acid, or the like. The reaction is usually carried out at room temperature, between fifteen to thirty degrees centigrade, however, lower or higher temperatures are-operative for the process. The hypohalous acid releasing agent is generally used in one molar or slightly increased, for example, percent increased, amounts compared to a mole of steroid. A large excess of the hypohalous acid releasing agent, while operative, is undesirable, since the excess of hypohalous acid has a tendency to react on other positions of the molecule. The reaction period is rather short and may vary between about five minutes to one hour. At the end of the reaction time the excess of hypohalous acid is destroyed by the addition of sodium sulfite or other sulfites or hydrosulfites. The thus produced product, 6- flllOIO-9oz-l18.lO-l 1fi-hydroxy-4-pregnene 3,20 dione (6- fiuoro-9whalo-llfi-hydroxyprogesterone), wherein the halogen atom is of atomic number 17 to 53, is isolated from the reaction mixture by adding an excess of water and extracting the compound with organic solvents or by recovering the precipitated compound through filtration. The crude product thus obtained may be recrystallized from organic solvents, such as acetone, Skellysolve B hexane hydrocarbons or the like to give pure 6-fluoro 9a-halo-11[3-hydroxy-4-pregnene-3 ,ZO-dione.

Oxidizing the 6-fluoro-9ot-halo-llB-hydroxy-4-pregnene- 3,20-dione with ,chromic acid produces the corresponding adrenocortically active 6-fluoro-9a-halo-4-pregnene-3,ll, ZO-trione (6-fluoro-9a-halo-1l-ketoprogesterone).

In order to obtain the 9a-fiuoro compounds, the 9,6, 11 fi-oxido intermediate of the aforementioned compound, 6-fiuoro-9f3,1lB-oxidot-pregnene-li,ZO-dione is prepared. In carrying out this reaction a 6-fluoro-9u-halod1fl-hydroxy-4-pregnene-3,ZOTdione wherein the halogen atom is of atomic number seventeen to 53, inclusive, is heated in solution with a mild base.

The bases useful for the cyclization include anhydrous potassium acetate, sodium bicarbonate, sodium acetate, or the like, with potassium acetate preferred. Solvents such as methanol, ethanol, acetone, tertiary butyl alcohol, or the like, may be used. The reaction time is between onehalf hour and 24 hours; generally a period between three and twelve hours is sufiicient. The thus obtained -fluoro- 95,1lB-oxido-4-pregnene-3,ZO-dione is isolated from the reaction mixture by diluting the reaction mixture with excess water and filtering the product when crystalline, or by extracting with methylene chloride or other water-immiscible solvents such as ether, Skellysolve B hexanes, pentanes, benzene, ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, pyridine, or the like. Evaporation of the solvent of the extracts produces the 6-fluoro- 913,11,8-oxido-4-pregnene-3,ZO-dione.

" over sodium sulfate.

The thus obtained 6-fluoro-9fl,11,3-oxido-4-pregnene-3, 20-,dione is thereupon reacted .with hydrogen fluoride .eitherfas gas or liquified at low temperature or with aqueous hydrofluoric acid in solution. As solvents for this reaction methylene chloride, ethylene dichloride, tetrahydrofuran, chloroform, carbon tetrachloride, or thelike, are, useful. The reaction may be carried out at room temperature (twenty to thirty degrees centigrade) or, in the preferred embodiment of the invention, in tetrahydrofuramat low temperature, e. g., plus ten. to minus eighty degrees centigrade with stirring. The period of reaction is from one to 24 hours, with a period from one to twelve hours ,usually sutficient. After the reaction is terminated, the mixture is'poured into water and neutralized with a dilute base, e. g., sodium or potassium hydroxide or carbonateor a bicarbonate such as sodium bicarbonate, potassium bicarbonate, or thelike. The reaction mixture is then extractedwith a water-immiscible solvent such as methylene chloride, the organic layer is separated from the water mixture, washed with water, dried, and evaporated to give the crude 6,9OL-difiUCTO-ll/3- hydroxy 4 pregnene-3,20-dione (6,9a-difluoro-l1fi-hydroxyprogesterone). The thus obtained crude compound can be purified through recrystallization or chromatography.

Oxidation of the 6,9a-difluoro-l1B-hydroxy-4epregnene- 3,20-dione with chromic acid produces the corresponding 6,9a-difiuoro-4-pregnene-3,11,20-trione (6,9u-difiuoro-l 1- ketoprogesterone) l-dehydro-G-fiuoro-llit-hydroxyprogesterone and l-dehydro-6-fluoro-1l-ketoprogesterone are produced, for example, by fermentation of the corresponding 6-fiuoro-l 1(3- hydroxyprogesterone or 6-fluoro-1l-ketoprogesterone with Septomyxa afiinis, A. T. C. C. 6737, or chemically, by treatment with selenium dioxide.

Similarly, 1 dehydro 6-flll0l0-9u-h2lO-1IB-llYdITOXY- progesterone and 1 dehydro 6-fliJOI'O-9OL-h210-1l-kfit0- progesterone are produced, for example, by fermentation of the corresponding 6-fluoro-9a-halo-1Iii-hydroxyprogesterone or 6-fluoro-9a-hal0-1l-ketoprogesterone with Septomyxa afiinis, A. T. C. C. 6737, or chemically, by treatment with selenium dioxide. Alternatively, the order of steps may be reversed. Thus 1-dehydro-6-fluoro-9tx-halollfi hydroxyprogesterone and 1-dehydro-6-fluoro-9ahalo-1 l-ketoprogesterone are produced, for example, by introduction of the 9a-halogen atom into 1-dehydro-6- fiuoro-llfi-hydroxyprogesterone in the manner described hereinbefore for the production of 6-fluoro-9a-l1alo-l1fihydroxyprogesterone and 6-fluoro-9a-halo-1l-ketcprogesterone.

The following examples are illustrative of the products and process of the present invention, and are not to be construed as limiting.

EXAMPLE 1 1] -ket0pr0gester0ne 3,20-bis- (ethylene ketal) A solution was prepared containing grams .of 11- ketoprogesterone, five grams of para-toluenesulfonic acid in 1.1 liters of benzene and 200 milliliters of ethylene glycol. This solution was refluxed vigorously with rapid stirring for four hours, using a Water trap to remove the water formed in the reaction. After this period .of-reflux, the solution was cooled and washed with live percent aqueous sodium bicarbonate, then water,. and dried The solvents were removedby distillation and hot ethyl acetate was added. The ethyl acetatesolution was chilled, diluted with ether, and filtered to give 68.7 grams of ll-ketoprogesterone 3,20-bis- (ethylene ketal), melting at to degrees centigrade.

In the same manner as shown above, treating 1l-l-;eto-

progesterone with alkanediols containing up to and including eight carbon atoms in the presence of benzene and paratoluenesulfonic acid is productive of the corresponding ll-ketoprogesterone 3,20-bis-(alltylene ketal).

The alkanediols 'usedl' are preferably 'vicinal alkanediols such as alkane-1,2-diols, or the alkane-1,3-dio1s, such as, for example, ethylene glycol, propane-1,2-diol, propane- 1,3-diol, butane-1,2-diol, butane-2,3-diol, pentane-1,2-dio1, 3-methy1pentane-L2-diol, hexane-1,3-diol, octane-1,2-diol, and the like... I

, EXAMPLE 2 IIfl-hydroxyprog'esterone 3,20-bis-(ethylene ketal) In the same manner shown in Example 1, treating 1113- hydroxyprogesterone in benzene with ethylene glycol and para-toluenesulfonic acid is productive of llfi-hydroxyprogesterone 3,20-bis-(ethylene ketal). I Similarly, substituting for ethylene glycol the alkanediols containing up to and including eight carbon atoms, asillu'strated in Example 1, is productive of the correspending 11;? hydroxyprogesterone 3,20-bis-(alkylene ketals). t

, Alternatively, 11 ketoprogesteron 3,20 bis (ethylene ketal). is treated with excess lithium aluminum hydride in ether. solution for one hour at room temperature, the excess, lithium aluminum hydride is destroyed by addition of water, or ethyl acetate followed by water, and the ether solution is separated, washed with water, and evaporated to give up hydroxyprogesterone 3,20 bis (ethylene ketal). I v I EXAMPLE 3 3.3. oxidopregriane 3,11,20 trione 3,20-bis (ethyl-' ene ketal) To a suspension of ten grams of anhydrous sodium acetate in 100.,milliliters of-forty percentperacetic acid, cooled in an ice bath, was added a solution of fifty of ll' ketoproge sterone 3,20-bis-( ethylene ketal) in milliliters 'ofchlorofo'rm; The heterogeneous mixwasstirred'vigorously for two and one-half hours at ice bathtemperature, the mixture was washed with water, five' 'perccnt aqueous sodium hydroxide, and water, and the n dried with magnesium sulfate, filtered, and evaporated-to dryness "under reduced pressure to give a white 'solid'residue' which was boiled with about 500 milliliters 'of'methanol and cooled. The thus obtained precipitate collected by filtration and recrystallized from ethyl acetate to give 31.2 grams of 5 e,6a-oXidopregnane-3,11, 20 trione3,20-bis-(ethylene ketal) of melting point 208 "to 214 degrees centigrade. v t

. EXAMPLE 4 5a,6a oxido 11p hydroxypregnane 3,20

" bis-(ethylene ketal) 1 the same manner as shown in Example 3, treating 'l lfi -"hydr'oxypregnane- 3,20 dione 3,20 bis (ethyl- "ene' 'l'retal) or the lla-hy'droxy epimer thereof in chloroform solution with peracetic' acid and sodium acetate is dione 3,20-

productive of 5 ,605-Xldd- 1'1 p-hydroxypregnane-3,20-dion 3,20 bis-(ethylene-ketal), or the lla-hydroxy epimer, iw ve w I EXAMPLE fluoropregnane 3,11,20 trione 3,20- bis-(ethylene ketal) '58: hydroxy 613 through. a 300 gram column of synthetic aluminum silipate to give 4.10 grams'offractions eluated with two perasses oi cent and three percent acetone in Skellysolve B'hexanes. The thus obtained combined fractions were recrystallized from methanol containing a trace of pyridine to give 3.3 grams of- 5a-hydroxy-6B-fluoropregnane-3,11-20-trione 3,20-bis-(ethylene ketal), having a melting point of 138 to 142 degrees centigrade, and the analysis:

"Analysis.Calcd. for C H FO C, 66.35; H, 8.24; F, 4.20. Found: C, 66.34; H, 8.32; F, 4.24.

50:. hydroxy 6B fluoropregnane 3,11,20 trione 3,20-.bis-(ethylene ketal) was prepared by an alternative route involving ketalization of the corresponding trione. A solution of four grams of 5a-hydroxy-6fi-fluoropregnane-3,11,20-trione, from Example 10, 0.5 gram of paratoluenesulfonic acid and fifteen milliliters of ethylene glycol in 200 milliliters of benzene was stirred and refluxed rapidly. The condensate was passed through a Dean-Stark water trap to remove the water as it formed. During five hours of heating, 0.7 milliliter of water was collected. The reaction mixture was cooled, washed with dilute cold aqueous sodium bicarbonate, water, and dried. The solution was evaporated and the residue was recrystallized from methanol containing a trace of pyridine to give two crops of 5a-hydroxy-6p-fluoropregnane-3,11,20- trione 3,20-bis-(ethylene ketal), one of 3.4 grams having a melting point ofv 128 to 133 degrees centigrade and one of 0.8 gram having a melting point of 124 to 131 degrees centigrade. Infrared spectrashowed that they were the same as the corresponding 3,20-bis-(ethylene ketal) of melting point 138 to 142 degrees centigrade prepared above. t

1 v EXAMPLE 6 5a,11fi dihydroxy 613 fluoropregnane 4 3,20 alione 3,20-bis-(ethylene ketal) To a solution of one gram of Sa-hYdIOXY-Gfi-flllOIO- pregnane 3,11,20 -trione 3,20 bis (ethylene ketal) in 100 milliliters of ether at room temperature was added 0.3 gram of lithium aluminum hydride with stirring. After 1.25 hours, ethyl acetate and more ether was added. Ice was then added slowly until the inorganic precipitate coagulated. The organic layer was decanted and washed three times with water, dried over magnesium sulfate, filtered and concentrated to dryness, giving a residue of 50:,115 dihydroxy 6 8 fluoropregnane 3,20 dione 3,20-bis-(ethylene ketal). Infrared analysis of the thus obtained crude productshowed the presence of hydroxyl and ketal bonds and the absence of ketone bonds. The crude product was usedwithout purification in the next step. Alternatively, 5a,11,3 dihydroxy 6,3 fluoropregnane- 3,20-dione 3,20-bis-(ethylene ketal) is obtained by treating 50:,60: oxido 11B hydroxypregnane 3,20 4 dione 3,20-bis-(ethylene ketal), in the same manner as shown in Example 5, with potassium bifluoride, acetic acid and acetic anhydride for two daysatroom temperature, then isolating the thus produced 5a,1l 8-dihydroXy-6fl-fluoropregnane 3,20 dione 3,20 bis (ethylene ketal) by methylene chloride extraction and chromatographic separation;

' EXAMPLE 7 A solution of one gram of crude 5a,11B-dihydroxy-6fifluoropregnane-3,20-dione 3,20-bis-(ethylene ketal) in a mixture of thirty milliliters of methanol and 2.5 milliliters of one normal aqueous sulfuric acid was boiled for thirty minutes, then concentrated to give 0.6 gram of 50:,11B --dihydroxy 6p fluoropregnane 3,20 dione as crystals melting at 240 to 255 degrees centigrade, and a second crop of 0.1 gram. The two crops were combined and crystallized from methanol to give 0.4 gram of 5u,11fl dihydroxy 6B fluoropregnane 3,20 dione having a melting point of 266 to 269 degrees centigrade, '[al plus 84 degrees percent ethanol) and the following analysis:

11 ,Aygqlysis-Caled. for C H FO C, 68.82; H, 8.53; F, 5.18. Found: C,68.70; H, 8.88; F, "531 To a slurry of,200. milligrams of SuJIB-dihydmxy- 6fi-fluoropre gnane 3,20rdione in forty millilitersof 95 percent ethanol was, added two milliliters of one :normal aqueous. sodium hydroxide. The reaction mixture .:Was stirred at room temperature for seven hours. The solution was clear ,after two hours, and after sevenhours, twov drops of laceticacid was added and the reaction mixture. concentrated under diminished pressure to about three milliliters. One milliliter of water was added, resulting in crystallization. The crystals.werecollected. by filtration, washed with alcohol-water mixture, dried and recrystallized from a mixture ofacetone-Skellysolve B hexanes to ,give" 6 8-fluoro-1IB-hydroxyprogesterone of melting-point 1=91 to 1 96 degrees Centigrade, [a1 ..plus

l21 :degre es (chloroform) (1 11,600 at .234 millimicrons .in-95 percent alcohol,- and having the following. analysis: A-naIysis.Calcd. for (3 1-1 1 C, 72.38; H, 8.39; F, 5.45. Found: C, 72.73; H,.8;49; F, 5,29.

-'EXAMPLE 9 6 a-fluora-I lfi hydroxyprogesterone A slurryof 350 milligrams of a,11;9-dihydroxy-6;9- fluoropregnane-BJO-dione with milliliters of chloro- .form. was.=cooled.in an ice-salt bath and saturated with hydrogen chloride gas. The steroid required aboutfive minutes to dissolve. After thirty minutes a fast stream of nitrogenwas passed through the reaction mixtulfe, re-

moving most of the hydrogen chloride. 'The solution was washed three times with water, dried over magnesium sulfate, filtered,and-concentrated to dryness. 'The*thus obtained residue -was-crystallized from an acetone-Skellysolve1 B-hexanes mixture and gavetwo crops of crystals, afirst crop of' 0.2 gram with'a melting-point of l73 to 1'77 'degreescentigrade and a second "crop of 0.1 gram 'witha'melting'point of 176 to 1'78'degrees centi grade. The two'crops-were combined and recrystallized from a mixture of acetone and Skellysolve "Bhexanes togive 6a-fiuoro-11,8-hydroxyprogesterone having a melting point of 181 to 183 degrees centigrade, [0:1 plus 194 degrees (chloroform), a 15,075 at 237 millimicrons in 95 percent alcohol, and the following analysis:

Analysis.Calcd. "for C l-1 F0 2 C, 72.38; H, 8239; F, 5.49. Found: -C,*72.05; H, 8.90;'F,-4.86.

Alternatively, treating a solution of 6B-fluoro-11p-hydroxy-progesterone in chloroform with hydrogen chloride gas,;inthe-manner described above, is productive of 6a- "fluoro l l-e-hydroxyprogesterone.

EXAMPLE 10 5a-hydroxy-6j8-fluoropregnane-3,11,20-trione A mixture-of eighty grams of potassium bifluoride in "500, milliliters of acetic acid was stirred until it ;.-had nearly dissolved. Sixty gramsof 5a,6a-oxidopregnane- 3,11,20-trione 3,20-bis-(ethylene ketal) was then added and the reaction mixture stirred for eighteen hours at room temperature, followed by dilution with 700 milliliters of methylene chloride, washing three times with water, drying over-magnesium sulfate, filtering, and concentrating to dryness to give an oily residue. The thus obtained residue was dissolved in 200 milliliters of '95 percent alcohol, and forty milliliters of one normal aqueoussuluric acid was added. The solution was warmed on the steam bath for one and one-half hours and-diluted with sixty milliliters ofwaterto give a precipitate of SOC-hydroxy-6B fiuoropregnane-3,11,20-trione. The precipitate .was collected by filtration from the, still warm solution, .washed with about twenty milliliters of 1:1 ethanol-water mixture and dried to give 12.8 grams of crystals having .a melting point.of 271 to 273 degrees centigrade, [al plus 103 degrees in pyridine, and the following-analysis:

12 Analysis-Calcd. for C H Q F: C, 69.20; H, 8.02; 1 ,5121. "-Found: C, 69.48;'I- I,"8.'25; F, 4.54.

EXAMPLE 11 I 6 ,B-fluoro-I 1 -ketopr,ogesterone To a solution of 13.5 grams of 5a-hydroxy-6fi fluoropregnane-3,1l,20-trione in 170milliliters of pyridine was added 13.5 grams of N-bromoacetamide. at room temperature. The reaction mixture was allowed to stand forty to fifty minutes, and then was 'cooled'in an ice bath while a stream of sulfur dioxide gas 'was:passed over"the surface of the solution. After:22.5.'grams"ofsulfur'dioxide had been absorbed, the solution wasstored 'at room temperature for one and onequarter hours. -The solution was again cooled with an ice bath andfdiluted with 450 milliliters of ten percent aqueous'sulfuric acid. "The solution was next saturated with-salt and extracted'three times with methylene chloride. The methylene chloride extracts were combined and washed once with dilute aqueous sulfuric acid and "twice .with water, ;then-dried and evaporated to dryness. The thus obtained ;residue was recrystallized from ethyl'acetate to'*give*8';l5' grams of 6fi-fluoro-1l-ketoprogesterone' having a m'eltingipoint of 181 to 183.5 degrees centigrade, lal 'plus '151'degress in chloroform, a 13,200 at 228 millirnirons in percent ethanol, and the following analysis:

Analysis.Calcd. for C iH 'FO C, 72.80; H, 786; R548. Foundz'C, 72.69; H, 8.09;'-F, 5;55.

EXAMPLE 12 6a-flu0ro-1 I-ketoprogesterone A.solution of one gram of 6fi-fluoro-ll-ketoproglesterr one in ten milliliters of chloroform was co.oled:in,.an-.ice bath and saturated with hydrogen chloridmgas. .The reaction mixture was allowed to stand twenty minutes, and nitrogen was then bubbled through .thet-mixture to remove most of the hydrogen chloride. ,The chloroform solution was next washed with -water, -dilute aqueous sodiumbicarbonate, and brine, and then driedand evapw rated to dryness. The. thus obtained residue; .was crystallized first from methanol,-then from ethyl aceta te,.--,to give 0.3;gram of, 6a-fluoro-1l-ketoprogesterone havingna melting point of-184 to 187 degrees centigrade, t] 5. plus 248 degrees in chloroform, a 14,675;at, 223 millimicrons in 95 percent ethanol, and the following analysis:

Alternatively, treating-a-solution of 0.5 gram of 6m fluoro-l lfl-hydroxyprogesterone dissolved in,.3Q milliliters of aceticacid at room temperature.with ausolution .of 0.15 gram of chromium trioxide in 0.5 milliliter of water for thirty minutes, destroying theexcess chromium,trioxide with methanol, diluting the reaction mixture with water, extracting with methylene chlorideandevaporating the methylene chloride solution to dryness,. f ollowed by crystallizing the residue from methanol, is productive of 6a-fluoro-1l-ketoprogesterone.

'-It. is to be understood. that. the invention-sis -.not.-ito be limited to the exact -:details..of. operation or exact compoundsshown and described, as obviousmodifications andequivalents will .be' apparent to one skilled-in the art; the invention is therefore to be limited only by the scope of the appended claims.

Weclaim:

1. An ll-oxygenated fi-fluoroprogesterone,wherein the ll-oxygen function is a, member of; the .groupwcon sisting of hydroxy and keto.

. 6 fluor o'-1lfi-hydroxyprogesterone.

. 6,B-fluoro-11p hydroxyprogesterone. 6a-fluoro-1lp-hydroxyprogesterone. 6.-fluoro-1l-ketoprogesterone.

. ,6B-fluoro-1l-ketoprogesterone.

. Gu-fluoro-ll ketoprogesterone.

wherein R is an alkylene radical containing one to eight carbon atoms, inclusive, and the attaching oxygen-tocarbon bonds are separated by a chain of at least two and not more than three carbon atoms, and R is a member of the group consisting of keto and hydroxy.

9. 50:,116 dihydroxy 6 3 fiuoropregnane 3,20 one 3,20-bis-(ethylene ketal), v

10. 50c hydroxy 6,3 fiuoropregnane 3,11,20 trione 3,20-bis-(ethylene ketal).

11. An ll-oxygenated 5u-hydroxy-6-fluoropregnane- 3,20-dione wherein the ll-oxygen substituent is a member of the group consisting of hydroxy and keto.

12. 5a,11fl-dihydroxy-6 8-fluoropregnane-3,20-dione.

13 5 a-hydroxy-6B-fluoropregnane-3 ,1 1,20-trione.

14. A process for the production of ll-oxygenated 6- fluoroprogesterone, wherein the ll-oxygen substituent is a member of the group consisting of hydroxy and keto, which comprises: (1) reacting a compound of the formula:

wherein R is an alkylene radical containing one to eight carbon atoms, inclusive, and the attaching oxygen-to-carbon bonds are separated by a chain of at least two and not more than three carbon atoms, and R is a member of the group consisting of keto and hydroxy, with a fluorinating agent to produce a 5a-hydroxy-6fl-fluoro compound of the formula:

C\ /R O B wherein R and R are defined as above; (2) reacting the thus obtained fluorohydrin with a hydrolyzing agent to produce an ll-oxygenated a-hydroxy-6B-fiuoropregnane- 3,20-dione wherein the ll-oxygen substituent is a member of the group consisting of hydroxy and keto; and (3) reacting the thus obtained compound with a dehydrating agent to produce an 11 oxygenated 6-fluoro progesterone wherein the ll-oxygen substituent is a member of the group consisting of hydroxy and keto.

15. A process for the production of ll-oxygenated 6- fluoroprogesterone', wherein the ll-oxygen substituent is a member of the group consisting of hydroxy and keto, which comprises: (1) reacting a compound of the formula:

I CH1 CHI C\ /R O R! 0 R/ i i wherein'R is an alkylene radical containing one-to eight carbon atoms, inclusive, and the attaching oxygen-to-' carbon bonds are separated by a chain of at least two and not more than three carbon atoms, and R is a member of the group consisting of keto and hydroxy, with potassium bifluoride in acetic acid to produce a compound of the formula:

wherein R is an alkylene radical containing one to eight carbon atoms, inclusive, and the attaching oxygen-to-car- -bon bonds are separated by a chain of at least two and not more than three carbon atoms, and R is a member 15 of the group consisting of hydroxy and keto, which comprises: reacting'a compound of the formula:

wherein R and R are defined as above, with hydrogen fluoride.

17. A process for the production of ll-oxygenated 6-fluoroprogesterone which comprises: reacting ll-oxygenated a-hydroxy-6fi-fluoropregnane-3,20-dione wherein the ll-oxygen substituent is a member of the group consisting of hydroxy and keto, with a dehydrating agent to give the corresponding ll-oxygenated 6-flu0roprogesterone.

18. A process for the production of 6-fluoro-11-keto- 16 progesterone which comprises: reacting 5a-hydroxy-6flfluoropregnane-3,11,20-trione with an acid dehydrating agent.

19. A process for: the production of 6-fluoro-11-ketoprogesterone which comprises: reacting 5a-hydroxy-6B- fluoropregnane-3,11,20-trione with a dilute base.

20. A process for the production of 6-fiuoro-11-ketoprogesterone which comprises: reacting 5a-hydroxy-6f3- fluor0pregnane-3,11,20-trione with an N-bromoamide and sulfur dioxide.

21. A process for the production of 6-fluoro-l1fl-hydroxyprogesterone which comprises: reacting :,11/3-dihydroXy-6-fiuor0pregnane-3,20-dione with an acid dehydrating agent.

22. A process for the production of 6-fluoro-11flhydroxyprogesterone which comprises: reacting 50:,113- dihydroxy-6-fiuoropregnane-3,ZO-dione Witlra dilute base.

23; A process "for the production of ll-oxygenated cfluoroprogesterone which comprises: reacting an ll-oxygenated 6fl-fluoroprogesterone wherein the ll-oxygen substituent is a member of the group consisting of hydroxy and keto with hydrogen chloride.

24. GB-fluoro-lla-hydroxyprogesterone.

25 6ot-fiuoro-1 1a-hydroxyprogesterone.'

No references cited. 

1. AN 11-OXYGENATED 6-FLUOROPROGESTERONE, WHEREIN THE 11-OXYGEN FUNCTION IS A MEMBER OF THE GROUP CONSISTING OF HYDROXY AND KETO.
 8. A COMPOUND OF THE FORMULA: 